Nivedita Patni, MD,* Kathleen Collins, MD,† Perrin White, MD*

*Division of Pediatric Endocrinology, Department of Pediatrics, University of Texas Southwestern

Medical Center, Dallas, TX†Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University,

Palo Alto, CA

PRESENTATION

An 8-week-old boy presents with 2 days of worsening jaundice, lethargy, and poor

feeding, without fever, vomiting, or diarrhea. At term he weighed 3,400 g (43rd

percentile), had hypoglycemia onday 1, and received hyperbilirubinemia phototherapy

for 5 days. Physical examination is noteworthy for a lethargic and jaundiced boy

weighing 4,300 g (8th percentile). The liver edge is 4 cm below the costal margin. The

phallus is 1.7� 0.7 cm, with no hypospadias, normal scrotum, and descended testes.

Initial laboratory results are as follows: blood glucose, less than 20 mg/dL

(<1.11 mmol/L); total/direct bilirubin, 17.8/13.5 mg/dL (304.4/230.9 mmol/L);

alanine aminotransferase/aspartate aminotransferase, 258/686 U/L (4.31/11.46

mkat/L); free thyroxine, 0.96 ng/dL (12.4 pmol/L); and thyrotropin, 4.36 mIU/mL

(4.36 mIU/L).

An intravenous glucose infusion is started, and the patient is admitted to the

hospital. Liver ultrasonography reveals nonspecific coarse echogenicity with

gallbladder wall thickening. Liver biopsy shows marked hepatocellular cholesta-

sis, disarray and giant cell transformation, mild portal inflammation and portal

fibrosis with early bridging fibrosis, and no abnormal storagematerial. Testing for

herpes simplex virus types 1 and 2, enterovirus, Epstein-Barr virus, cytomega-

lovirus, adenovirus, human immunodeficiency virus, and hepatitis viruses is

negative; levels of urine succinylacetone and organic acids are normal, as are

plasma galactose-1-phosphate uridylyltransferase (GALT) and acylcarnitine levels.

He is tested for ATP8B1, ABCB11, ABCB4, and JAG1 mutations. Hypoglycemia

continues despite an intravenous glucose infusion rate of 16 mg/kg per minute.

After stopping his infusion for 30 minutes, the serum glucose level is 23 mg/dL

(1.3 mmol/L). Concurrent laboratory results include insulin, 0.8 mIU/mL (5.6

pmol/L); b-hydroxybutyrate, 0.1 mmol/L; free fatty acids, 0.56 mg/dL (0.02

mmol/L); and growth hormone, 1.55 ng/mL (1.55 mg/L). A low-dose cosyntropin

test and brain magnetic resonance imaging (MRI) (Figure) are performed.

DISCUSSION

Differential DiagnosisNeonatal cholestasis can be caused by obstructed bile flow or functionally

impaired hepatic bile secretion secondary to structural, infectious, genetic,

3 Hypoglycemia in an Infant with Cholestasis

AUTHOR DISCLOSURE Dr Patni has disclosedno financial relationships relevant to thisarticle. Dr Collins has disclosed that shereceived National Institutes of Health (NIH)training grant 2T32AR050942-11 for apediatric fellowship research project relatedto adult and pediatric rheumatology. Dr Whitehas disclosed that he has a grant from JanssenPharmaceuticals for an NIH-funded clinicaldrug trial. This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.

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metabolic, or endocrine abnormalities. Biliary atresia is a

fibro-obliterative disease of the extrahepatic biliary tree that

presents with persistent jaundice, pale stools, and dark

urine. Key diagnostic findings include ultrasonographic

features of abnormal gallbladder size and shape, the "tri-

angular cord" sign, poor gallbladder contractility, and

absence of the common bile duct. Hepatobiliary scintigra-

phy shows lack of tracer excretion from liver to intestines,

and liver biopsy demonstrates bile duct proliferation, a small

cell infiltrate, portal fibrosis, and absence of sinusoidal

fibrosis. (1)

Metabolic conditions such as galactosemia, long-chain

3-hydroxyacyl-CoA dehydrogenase deficiency (fatty acid oxi-

dation defects), and tyrosinemia type 1 can cause hypogly-

cemia along with cholestasis; these are usually detected by

newborn screening in the United States. Galactosemia

may present with vomiting and jaundice within a few days

of milk ingestion. Hepatomegaly is often present, and

Escherichia coli sepsis occurs frequently. Galactosemia is

diagnosed by reduced activity of GALT. (2) Long-chain

3-hydroxyacyl-CoA dehydrogenase deficiency can present

with hypoglycemia and liver disease along with elevated

levels of long-chain acylcarnitines. (3) Tyrosinemia type 1,

resulting from deficiency of fumaryl acetoacetate hydrolase,

usually presents in infancy with severe liver dysfunction,

growth failure, rickets, and renal tubular dysfunction. It is

characterized by elevated tyrosine, methionine, and phenyl-

alanine levels in plasma; increased succinylacetone levels in

the blood and urine; and elevated tyrosine metabolite and d-

aminolevulinic acid levels in urine. Definitive diagnosis is

made by measuring fumaryl acetoacetate hydrolyase activity

in liver biopsy specimens or cultured fibroblasts. (4)

Progressive familial intrahepatic cholestasis is a group of

rare autosomal recessive disorders presenting with intra-

hepatic cholestasis and features such as hearing loss,

diarrhea, and growth failure, and it is caused by mutations

in the ATP8B1, ABCB11, or ABCB4 gene. (5) Alagille syn-

drome is an autosomal dominant disorder characterized by

conjugated hyperbilirubinemia owing to bile duct paucity;

vertebral anomalies; congenital cardiac defects, particularly

pulmonary stenosis; ophthalmologic abnormalities such as

posterior embryotoxon; and characteristic facial features.

Heterozygous inactivating mutations in the JAG1 gene are

found in 94% to 96% of patients. (6)

Biliary atresiawas ruled out by liver ultrasonography.A viral

hepatitis panel was negative; normal urine succinylacetone

and organic acid levels and plasma GALT and acylcarnitine

levels ruled out metabolic diagnoses. There were no muta-

tions in the ATP8B1, ABCB11, ABCB4, or JAG1 genes.

Actual DiagnosisThe infant was diagnosed as having hypopituitarism.

The ConditionThe brainMRI (Figure) showed a diminutive pituitary gland

(yellow arrowhead), nonvisualization of the normal pituitary

stalk, and an ectopic neurohypophysis. The optic chiasm

and optic nerves were markedly diminutive (red arrows),

and the olfactory bulbs were absent. The cortisol level

increased from 1.3 mg/dL (36 nmol/L) to only 6 mg/dL

(166 nmol/L) (reference range, >18 mg/dL [>497 nmol/L])

after low-dose cosyntropin stimulation.

Hypoglycemia is best evaluated with additional concur-

rent blood testing. Patients with hypopituitarism have low free

fatty acid, lactate, insulin, cortisol, and growth hormone levels

in the setting of hypoglycemia. Hypocortisolism can then be

confirmed with a low-dose cosyntropin stimulation test. A

brain MRI delineates anatomical causes of hypopituitarism.

A microphallus (ie, penile length <2.5 cm [7]), blunted

growth hormone response to hypoglycemia, poor cortisol

Figure. Brainmagnetic resonance imaging. A. Sagittal T1-weighted image. The pituitary gland (yellow arrowhead) is diminutive in size and hypointense.A normal pituitary stalk is not visualized, indicating an ectopic neurohypophysis. B. Coronal T2-weighted image showing optic nerve hypoplasia (redarrows).

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response to cosyntropin, and abnormal MRI findings con-

firmed the diagnosis of hypopituitarism owing to septo-

optic dysplasia. Septo-optic dysplasia is a rare congenital

syndrome defined by the presence of at least 2 of 3 features:

1) midline forebrain defects such as absence of septum

pellucidum or corpus callosum, 2) optic nerve hypoplasia,

and 3) hypopituitarism. (8) Hypopituitarism should be

suspected in children with hypoglycemia and midline

defects such as cleft palate, midface hypoplasia, hypertelor-

ism or hypotelorism, or central incisor; optic nerve hypo-

plasia presenting with wandering nystagmus or poorly

reactive pupils; andmicrophallus. Newborn boys with hypo-

pituitarism usually have microphallus rather than ambigu-

ous genitalia because in the first trimester, placental human

chorionic gonadotropin stimulates testosterone secretion,

which promotes differentiation of the external genitalia.

Testosterone secretion and consequent penile growth after

the first trimester depend on luteinizing hormone secreted

by the fetal pituitary gland.

Cholestasis can rarely be a feature of hypopituitarism, (9)

the mechanism of which remains unclear. (10) Cortisol

modulates bile flow and bile acid synthesis (11); cortisol

deficiency might affect hepatic transport of bile acids across

bile canaliculi. Growth hormone plays an important role in

bilirubin glucuronidation and modulates the biosynthesis

and secretion of bile acid in rats (12); and growth hormone

deficiency can lead to abnormal biliary cell and bile duct

formation. (13) Untreated hypopituitarism has also been

linked to congenital hepatic fibrosis. (14) Thyroxine defi-

ciency (not present in this patient) delays maturation of

hepatic UDP-glucuronosyltransferase activity and causes

unconjugated hyperbilirubinemia. (15)

Patient CourseThe patient was treated with hydrocortisone, growth hor-

mone, and testosterone and was closely monitored for

diabetes insipidus and hypothyroidism. The cholestasis

resolved with growth hormone and hydrocortisone

replacement.

Lessons for the Clinician• Hypopituitarism should be suspected in children with

hypoglycemia and midline defects such as cleft palate,

midface hypoplasia, hypertelorism or hypotelorism, or

central incisor; optic nerve hypoplasia presenting with

wandering nystagmus or poorly reactive pupils; or

microphallus.• Cholestasis can be a rare presentation of hypopituitarism.

• Patients with hypoglycemia and conjugated hyper-

bilirubinemia should undergo endocrine evaluation for

hypopituitarism.

• Cholestasis resolves with growth hormone and hydro-

cortisone replacement.

ACKNOWLEDGMENT

The authors thank the patient’s parents for granting per-

mission to publish this information.

References for this article are at http://pedsinreview.aappubli-

cations.org/content/40/9/488.

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References1. Lakshminarayanan B, Davenport M. Biliary atresia: acomprehensive review. J Autoimmun. 2016;73:1–9

2. Karadag N, Zenciroglu A, Eminoglu FT, et al. Literature review andoutcome of classic galactosemia diagnosed in the neonatal period.Clin Lab. 2013;59(9-10):1139–1146

3. Sewell AC, Bender SW, Wirth S, Münterfering H, Ijlist L, WandersRJ. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: asevere fatty acid oxidation disorder. Eur J Pediatr.1994;153(10):745–750

4. Sniderman King L, Trahms C, Scott CR. Tyrosinemia type I. In:Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews[Internet]. Seattle, WA: University of Washington, Seattle; 1993–2017. Available at:https://www.ncbi.nlm.nih.gov/pubmed/20301688 Accessed June 6, 2018

5. Amer S, Hajira A. A comprehensive review of progressive familialintrahepatic cholestasis (PFIC): genetic disorders ofhepatocanalicular transporters. Gastroenterol Res. 2014;7(2):39–43

6. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinicalperspectives. Appl Clin Genet. 2016;9:75–82

7. Feldman KW, Smith DW. Fetal phallic growth and penile standardsfor newborn male infants. J Pediatr. 1975;86(3):395–398

8. Fard MA, Wu-Chen WY, Man BL, Miller NR. Septo-optic dysplasia.Pediatr Endocrinol Rev. 2010;8(1):18–24

9. Binder G, Martin DD, Kanther I, Schwarze CP, Ranke MB. Thecourse of neonatal cholestasis in congenital combined pituitaryhormone deficiency. J Pediatr Endocrinol Metab.2007;20(6):695–702

10. Copeland KC, Franks RC, Ramamurthy R. Neonatalhyperbilirubinemia and hypoglycemia in congenitalhypopituitarism. Clin Pediatr (Phila). 1981;20(8):523–526

11. Dumont M, Erlinger S. Influence of hydrocortisone on bileformation in the rat. Biol Gastroenterol (Paris). 1973;6(3):197–203

12. Gueraud F, Masmoudi T, Goudonnet H, Paris A. Differential effectof hypophysectomy and growth hormone treatment on hepaticglucuronosyltransferases in male rats: evidence for an action at apretranslational level for isoforms glucuronidating bilirubin.Biochem Pharmacol. 1997;53(11):1637–1647

13. DeSalvo D, Pohl JF, Wilson DP, et al. Cholestasis secondary topanhypopituitarism in an infant. J Natl Med Assoc.2008;100(3):342–344

14. Minami K, Izumi G, Yanagawa T, Shimoyamada Y, Yoshikawa N.Septo-optic dysplasia with congenital hepatic fibrosis. Pediatr Neurol.2003;29(2):157–159

15. Labrune P, Myara A, Huguet P, et al. Bilirubin uridine diphosphateglucuronosyltransferase hepatic activity in jaundice associated withcongenital hypothyroidism. J Pediatr Gastroenterol Nutr.1992;14(1):79–82

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DOI: 10.1542/pir.2017-02092019;40;488Pediatrics in Review 

Nivedita Patni, Kathleen Collins and Perrin WhiteCase 3: Hypoglycemia in an Infant with Cholestasis

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